Throughout this application, various publications are referenced by number. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
The regulation of the secretion of apolipoprotein B-containing lipoproteins is a topic of great importance, since their increased secretion plays a major role in dyslipidemia such as occurs in familial combined hyperlipidemia, diabetes and obesity.
Apolipoprotein B (apoB) is the major protein component of chylomicrons and very low density lipoprotein (VLDL) which transport triglycerides from the intestine and liver, respectively, into the bloodstream1,2. Intravascular remodeling of VLDL by lipolysis and lipid transfer results in the formation of low density lipoprotein (LDL), the major atherogenic lipoprotein in human plasma3. The overproduction of apolipoprotein B-containing lipoproteins (BLp) by the liver is thought to be a major cause of accelerated atherosclerosis. Increased hepatic BLp synthesis is the principal defect in subjects with familial combined hyperlipidemia7,8, and is also an important component of the dyslipidemia of diabetes and obesity9,10.
The regulation of BLp secretion, which takes place primarily on a post-transcriptional level11, is poorly understood. Apolipoprotein B exists in two forms, apoB100 and apoB484. Both are products of a single gene encoding a 14 Kb mRNA and share the same amino-terminal 2152 amino acids. Specific editing of human apoB100 mRNA in the intestine introduces a stop codon at residue 2153 to produce apoB485,6. The addition of lipid to apolipoprotein B in the secretory pathway of hepatocytes and enterocytes is a tightly coordinated event. The microsomal triglyceride transfer protein (MTP) is involved in an early phase of lipid addition to apolipoprotein B, and deficiency of MTP results in markedly reduced secretion and levels of BLp in human abetalipoproteinemia12,13.
During the intravascular lipolysis of chylomicrons and VLDL, there is transfer of excess surface phospholipids from these particles into high density lipoproteins (HDL)14. This process is mediated by a plasma phospholipid transfer protein (PLTP). Studies in PLTP knock-out (PLTP0) mice15 show that PLTP mediates the transfer of phospholipids from the apolipoprotein B-containing lipoprotein (BLp) into HDL, and demonstrate the importance of this process in the maintenance of HDL levels. However, a role of PLTP in the metabolism of BLp per se has not been previously considered. The present application discloses that PLTP deficiency has a major effect on the hepatic secretion of BLp, resulting in reduced BLp levels.